This invention relates to the preparation of mibefradil and its dihydrochloride salt.
U.S. Pat. No. 4,808,605 (to Hoffmann-La Roche) discloses various calcium antagonists including mibefradil, (1S,2S)-2-2-{3-(1H-benzimidazol-2-yl)propyl!-methylamino}ethyl!-6-fluoro -1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, the dihydrochloride salt of which is the active ingredient of the antihypertensive Pricor. The synthesis of mibefradil, as described in that patent, involves the reaction of (1S,2S)-6-fluoro-1-isopropyl-2-2-(4-toluenesulfonyloxy)ethyl!-1,2,3,4-tet rahydronaphthalene-2-ol with 3-(1H-benzimidazol-2-yl)propyl!methylamine in the presence of Hunig base (ethyldiisopropylamine) to form (1S,2S)-2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino }ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, which is then acylated with methoxyacetyl chloride in chloroform in the presence of ethyidiisopropylamine to form mibefradil.
The (1S,2S)-6-fluoro-1-isopropyl-2-2-(4-toluenesulfonyloxy)ethyl!-1,2,3,4-tet rahydronaphthalene-2-ol, as described in U.S. Pat. No. 4,680,310 (also to Hoffmnann-La Roche), is prepared by reacting (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with tert-butyl bromoacetate in the presence of activated magnesium to form tert-butyl (1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl )acetate, which is reduced with lithium aluminum hydride to form (1S,2S)-6-fluoro-2-(2-hydroxyethyl)-1-isopropyl-1,2,3,4-tetrahydronaphthal en-2-ol, and then reacted with 4-toluenesulfonyl chloride in pyridine to form the (1S,2S)-6-fluoro-1-isopropyl-2-2-(4-toluenesulfonyloxy)ethyl!-1,2,3,4-tet rahydronaphthalene-2-ol.
It would be of value to have a method for the preparation of mibefradil and mibefradil dihydrochloride that affords the desired compounds easily and in reproducible high yield and purity, and is readily adaptable to large scale commercial production.